PROJECT SUMMARY Trypanosoma cruzi is the protozoan parasite that causes Chagas disease, an illness that affects millions in the western hemisphere from Argentina to Canada. People can become infected with T. cruzi through the bite of its reduviid bug vector or through several other means, including maternal-fetal transmission and blood transfusion. Chagas manifests as a chronic cardiomyopathy in approximately one-third of infected individuals and is the leading cause of infectious myocarditis in the world. Others develop megadisease of the esophagus or colon. The two drugs used to treat T. cruzi infection, Nifurtimox and Benznidazole (Bz), have been the mainstay of therapy for decades, with no significant improvement to their well-documented neurotoxicity and carcinogenicity. Chagas is thus a silent epidemic that is in dire need of more advanced treatment options. We have developed a novel nanocarrier formulation (nanoBz) that permits the delivery of parasiticidal drugs that effectively kill T. cruzi parasites at 166-fold lower concentrations than required by the current free drug formulation. The goals of our proposed research are: Aim 1. To determine how the cellular biodistribution of nanoBz influences its trypanocidal activity during acute T. cruzi infection. Aim 2. To validate the sustained delivery of nanoBz for prophylactic and therapeutic treatment of chronic T. cruzi infection.